Epilepsy occurs in approximately 1% of the population worldwide, (Thurman at al., 2011) of which 70% are able to adequately control their symptoms with the available existing anti-epileptic drugs (AED). However, 30% of this patient group, (Eadie et al., 2012), are unable to obtain seizure freedom using the AED that are available and as such are termed as suffering from intractable or “treatment-resistant epilepsy” (TIRE).
Intractable or treatment-resistant epilepsy was defined in 2009 by the International League Against Epilepsy (ILAE) as “failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom” (Kwan at al., 2009).
Individuals who develop epilepsy during the first few years of life are often difficult to treat and as such are often termed treatment-resistant. Children who undergo frequent seizures in childhood are often left with neurological damage which can cause cognitive, behavioral and motor delays.
Childhood epilepsy is a relatively common neurological disorder in children and young adults with a prevalence of approximately 700 per 100,000. This is twice the number of epileptic adults per population.
When a child or young adult presents with a seizure, investigations are normally undertaken in order to investigate the cause. Childhood epilepsy can be caused by many different syndromes and genetic mutations and as such diagnosis for these children may take some time.
The main symptom of epilepsy is repeated seizures. In order to determine the type of epilepsy or the epileptic syndrome that a patient is suffering from, an investigation into the type of seizures that the patient is experiencing is undertaken. Clinical observations and electroencephalography (EEG) tests are conducted and the type(s) of seizures are classified according to the ILAE classification described below and in FIG. 1.
The International classification of seizure types proposed by the ILAE was adopted in 1981 and a revised proposal was published by the ILAE in 2010 and has not yet superseded the 1981 classification. FIG. 1 is adapted from the 2010 proposal for revised terminology and includes the proposed changes to replace the terminology of partial with focal. In addition the term “simple partial seizure” has been replaced by the term “focal seizure where awareness/responsiveness is not impaired” and the term “complex partial seizure” has been replaced by the term “focal seizure where awareness/consciousness is impaired”.
From FIG. 1 it can be seen that Generalised seizures, where the seizure arises within and rapidly engages bilaterally distributed networks, can be split into six subtypes: Tonic-Clonic (grand mal) seizures; Absence (petit mal) Seizures; Clonic Seizures; Tonic Seizures; Atonic Seizures and Myoclonic Seizures.
Focal (partial) seizures where the seizure originates within networks limited to only one hemisphere, are also split into sub-categories. Here the seizure is characterized according to one or more features of the seizure, including aura, motor, autonomic and awareness/responsiveness. Where a seizure begins as a localized seizure and rapidly evolves to be distributed within bilateral networks this seizure is known as a Bilateral convulsive seizure, which is the proposed terminology to replace Secondary Generalized Seizures (generalized seizures that have evolved from focal seizures and are no longer remain localized).
Focal seizures where the subjects awareness/responsiveness is altered are referred to as focal seizures with impairment and focal seizures where the awareness or responsiveness of the subject is not impaired are referred to as focal seizures without impairment.
Focal seizures may occur in epilepsy syndromes including: Lennox-Gastaut Syndrome; Tuberous Sclerosis Complex; Dravet Syndrome; CDKL5: Neuronal ceroid lipofuscinoses (NCL); febrile infection related epilepsy syndrome (FIRES); Aicardi syndrome and brain abnormalities.
Epileptic syndromes often present with many different types of seizure and identifying the types of seizure that a patient is suffering from is important as many of the standard AED's are targeted to treat or are only effective against a given seizure type/sub-type.
One such childhood epilepsy is Dravet syndrome. Onset of Dravet syndrome almost always occurs during the first year of life with clonic and tonic-clonic seizures in previously healthy and developmentally normal infants (Dravet, 2011). Symptoms peak at about five months of age. Other seizures develop between one and four years of age such as prolonged focal dyscognitive seizures and brief absence seizures.
In diagnosing Dravet syndrome both focal and generalised seizures are considered to be mandatory, Dravet patients may also experience atypical absence seizures, myoclonic absence seizures, atonic seizures and non-convulsive status epilepticus.
Seizures progress to be frequent and treatment-resistant, meaning that the seizures do not respond well to treatment. They also tend to be prolonged, lasting more than 5 minutes. Prolonged seizures may lead to status epilepticus, which is a seizure that lasts more than 30 minutes, or seizures that occur in clusters, one after another.
Prognosis is poor and approximately 14% of children die during a seizure, because of infection, or suddenly due to uncertain causes, often because of the relentless neurological decline. Patients develop intellectual disability and life-long ongoing seizures. Intellectual impairment varies from severe in 50% patients, to moderate and mild intellectual disability each accounting for 25% of cases.
There are currently no FDA approved treatments specifically indicated for Dravet syndrome. The standard of care usually involves a combination of the following anticonvulsants: clobazam, clonazepam, levetiracetam, topiramate and valproic acid.
Stiripentol is approved in Europe for the treatment of Dravet syndrome in conjunction with clobazam and valproic acid. In the US, stiripentol was granted an Orphan Designation for the treatment of Dravet syndrome in 2008; however, the drug is not FDA approved.
Potent sodium channel blockers used to treat epilepsy actually increase seizure frequency in patients with Dravet Syndrome. The most common are phenytoin, carbamazepine, lamotrigine and rufinamide.
Management may also include a ketogenic diet, and physical and vagus nerve stimulation. In addition to anti-convulsive drugs, many patients with Dravet syndrome are treated with anti-psychotic drugs, stimulants, and drugs to treat insomnia.
The first line treatment for focal seizures are AED such as carbamezapine or lamotrigine. Levetiracetam, oxycarbamezapine or sodium valproate are also considered to be of use. A combination of these medicaments may be required in order to treat focal seizures.
Common AED defined by their mechanisms of action are described in the following tables:
TABLE 1Examples of narrow spectrum AEDNarrow-spectrumAEDMechanismIndicationPhenytoinSodium channelComplex partialTonic-clonicPhenobarbitalGABA/Calcium channelPartial seizuresTonic-clonicCarbamazepineSodium channelPartial seizuresTonic-clonicMixed seizuresOxcarbazepineSodium channelPartial seizuresTonic-clonicMixed seizuresGabapentinCalcium channelPartial seizuresMixed seizuresPregabalinCalcium channelAdjunct therapy for partialseizures with or withoutsecondary generalisationLacosamideSodium channelAdjunct therapy for partialseizuresVigabatrinGABASecondarily generalized tonic-clonic seizuresPartial seizuresInfantile spasms due to Westsyndrome
TABLE 2Examples of broad spectrum AEDBroad-spectrumAEDMechanismIndicationValproic acidGABA/Sodium channelFirst-line treatment for tonic-clonic seizures, absenceseizures and myoclonicseizuresSecond-line treatment forpartial seizures and infantilespasms.Intravenous use in statusepilepticusLamotrigineSodium channelPartial seizuresTonic-clonicSeizures associated withLennox-Gastaut syndromeEthosuximideCalcium channelAbsence seizuresTopiramateGABA/Sodium channelSeizures associated withLennox-Gastaut syndromeZonisamideGABA/Calcium/SodiumAdjunctive therapy in adultschannelwith partial-onset seizuresInfantile spasmMixed seizureLennox-Gastaut syndromeMyoclonicGeneralised tonic-clonicseizureLevetiracetamCalcium channelPartial seizuresAdjunctive therapy for partial,myoclonic and tonic-clonicseizuresClonazepamGABATypical and atypical absencesInfantile myoclonicMyoclonic seizuresAkinetic seizuresRufinamideSodium channelAdjunctive treatment ofpartial seizures associatedwith Lennox-Gastautsyndrome
TABLE 3Examples of AED used specifically in childhood epilepsyAEDMechanismIndicationClobazamGABAAdjunctive therapy in complexpartial seizuresStatus epilepticusMyoclonicMyoclonic-absentSimple partialComplex partialAbsence seizuresLennox-Gastaut syndromeStiripentolGABASevere myoclonic epilepsy ininfancy (Dravet syndrome)
From these tables it can be seen that there are many AED are approved for use in focal (partial) seizures which work by a different mechanisms. Indeed the only AED that has been approved for use in the treatment of complex partial seizures (focal seizures with impairment) is the AED phenytoin.
Over the past forty years there have been a number of animal studies on the use of the non-psychoactive cannabinoid cannabidiol (CBD) to treat seizures. For example, Consroe et al., (1982) determined that GBD was able to prevent seizures in mice after administration of pro-convulsant drugs or an electric current.
Studies in epileptic adults have also occurred in the past forty years with CBD. Cunha et al. reported that administration of CBD to eight adult patients with generalized epilepsy resulted in a marked reduction of seizures in 4 of the patients (Cunha of al., 1980).
A study in 1978 provided 200 mg/day of pure CBD to four adult patients, two of the four patients became seizure free, whereas in the remainder seizure frequency was unchanged (Mechoulam and Carlini, 1978).
In contrast to the studies described above, an open label study reported that 200 mg day of pure CBD was ineffective in controlling seizures in twelve institutionalized adult patients (Ames and Cridland, 1986).
Based on the fact that chronologically the last study to look at the effectiveness of CBD in patients with epilepsy proved that CBD was unable to control seizures, there would be no expectation that CBD might be useful as an anti-convulsant agent.
In the past forty years of research there have been over thirty drugs approved for the treatment of epilepsy none of which are cannabinoids. Indeed, there appears to have been a prejudice against cannabinoids, possibly due to the scheduled nature of these compounds and/or the fact that THC, which is a known psychoactive, has been ascribed as a pro-convulsant (Consroe et al., 1977).
A paper published recently suggested that cannabidiol-enriched cannabis may be efficacious in the treatment of epilepsy. Porter and Jacobson (2013) report on a parent survey conducted via a Facebook group which explored the use of cannabis which was enriched with CBD in children with treatment-resistant epilepsy. It was found that sixteen of the 19 parents surveyed reported an improvement in their child's epilepsy. The children surveyed for this paper were all taking cannabis that was purported to contain CBD in a high concentration although the amount of CBD present and the other constituents including THC were not known for many of the cases. Indeed, whilst CBD levels ranged from 0.5 to 28.6 mg/kg/day (in those extracts tested), THC levels as high as 0.8 mg/kg/day were reported.
Providing children with TRE with a cannabis extract that comprises THC, which has been described as a pro-convulsant (Consroe et al., 1977), at a potentially psychoactive dose of 0.8 mg/kg/day, is a concern and as such there is a need to determine whether CBD is in fact efficacious.
In November 2013 the company GW Pharmaceuticals made a press release to state that they were intending to treat Dravet Syndrome with CBD as it had received orphan drug designation. A further press release was made in June 2014 which stated promising signals of efficacy in children with treatment-resistant epilepsy, including patients with Dravet syndrome.
The international patent application WO 2015/193667 describes the use of CBD in treatment resistant epilepsy. Patients included nine with Dravet syndrome out of 27 others.
The international patent application WO 2015/193668 describes the use of CBD in the treatment of absence seizures, Patients included those with Dravet syndrome in addition to ten other syndromes.
Maa and Figi (2014) discuss the case for medical marijuana in epilepsy and discuss the positive treatment of a girl Charlotte with Dravet syndrome who experienced frequent bouts of febrile and afebrile status epilepticus as well as tonic, tonic-clonic and myoclonic seizures (generalised seizures). She was given an extract from a cannabis plant dubbed “Charlotte's Web” which according to the suppliers, CW Botanicals, disclose that their extracts are rich in terpenes and contain from 10 to 200 times the amount found in other proprietary plants. In other words the suggestion is that the efficacy is based on a combination of CBD and the terpenes present in their extracts.
Press et al. (3 Apr. 2015), provides an in depth review of the parental reporting of pediatric patients with refractory epilepsy that were given oral cannabis extracts (OCE). Despite its in depth nature it concludes no studies demonstrate clear efficacy.
Significantly the document recognizes the effectiveness of an anti-seizure medication may be dependent upon: the drug itself, including CBD, (see Table 3); the epilepsy syndrome type (Table 2); and the seizure type (Table 2).
Very significantly the document in the discussion recognises caution needs to be taken when reviewing, particularly open label study data, since placebo rates may be high. Indeed it specifically comments that “four recently FDA approved anti-convulsant medications had placebo rates of 31.6%, 26.4%, 20% and 21% respectively” (page 51, left hand column).
Furthermore the analysis observed a surprising finding namely that “new residents of Colorado (those moving to obtain treatment) were more than three times as likely to report a greater than 50% seizure reduction than families with established care in Colorado” suggestive that studies such as that published in Porter and Jacobson (2013) may be highly flawed.
The skilled person would infer therefore from Press et al. would be that the drug type CBD plus the presence of “other OCE” (such as, other cannabinoids most likely THC and non-cannabinoids such as e.g. terpenes) appears a more interesting combination than CBD alone—responder rate 63% versus 35%.
That the epilepsy syndrome Lennox-Gastaut appears the most promising target with 89% responder rate versus Dravet (23% responder rate) or Doose (0% responder rate).
That of the seizure types studied ranged from 44% responder rate for atonic seizures to 17% responder rates in tonic seizures, amongst the seven seizures types reviewed.
The assessment looked at three distinct groups, namely; the OCE type, Table 3 (four OCE types); the epilepsy syndrome, see for example, page 50 right hand column line 3 (three syndrome types); and the seizure type, see page 51, Table 2 (seven seizure types).
In all this provides the reader with information on 84 different alternative combinations.
The problem facing the skilled practitioner looking at cannabis medicines in the field of epilepsy where many patients are refractory to existing medications is to select the appropriate cannabinoid and its form targeted to a given seizure type in a given patient group.
Perhaps therefore it is not surprising that in the Cochrane report (Gloss and Vickrey) published March 2014 undertook a full review on the efficacy of cannabinoids in the treatment of epilepsy concluded “no reliable conclusions can be drawn at present regarding the efficacy of cannabinoids as a treatment for epilepsy.”
Surprisingly the applicant has shown that CBD is particularly effective in the treatment of focal seizures in Dravet syndrome patients, particularly children and more particularly those which are resistant to existing treatments.